Loss of α(E)-catenin promotes Fas mediated apoptosis in tubular epithelial cells

• Published in: Apoptosis (London) 2015-07, Vol.20 (7), p.921-929
• Main Authors: Wang, Xinhui, Parrish, Alan R.
• Format: Article
• Language: English
• Subjects: Acute Kidney Injury - pathology; alpha Catenin - genetics; Animals; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis Regulatory Proteins - agonists; Apoptosis Regulatory Proteins - metabolism; Biochemistry; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cell Biology; Cell Line; Cisplatin - pharmacology; Epithelial Cells - metabolism; fas Receptor - metabolism; Gene Knockdown Techniques; Kidney Tubules - drug effects; Kidney Tubules - metabolism; Oncology; Original Paper; Rats, Inbred F344; Signal Transduction; Virology
• ISSN: 1360-8185; 1573-675X
• DOI: 10.1007/s10495-015-1129-x

The aging kidney undergoes structural and functional alterations which make it more susceptible to drug-induced acute kidney injury (AKI). Previous studies in our lab have shown that the expression of α(E)-catenin is decreased in aged kidney and loss of α(E)-catenin potentiates AKI-induced apoptosis, but not necrosis, in renal tubular epithelial cells (NRK-52E cells). However, the specific apoptotic pathway underlying the increased AKI-induced cell death is not yet understood. In this study, cells were challenged with nephrotoxicant cisplatin to induce AKI. A ~5.5-fold increase in Fas expression in C2 (stable α(E)-catenin knockdown) relative to NT3 (non-targeted control) cells was seen. Increased caspase-8 and -9 activation was induced by cisplatin in C2 as compared to NT3 cells. In addition, decreased Bcl-2 expression and increased BID cleavage and cytochrome C release were detected in C2 cells after cisplatin challenge. Treating the cells with cisplatin, in combination with a Bcl-2 inhibitor, decreased the viability of NT3 cells to the same level as C2 cells after cisplatin. Furthermore, caspase-3/-7 activation is blocked by Fas, caspase-8, caspase-9 and pan-caspase inhibitors. These inhibitors also completely abolished the difference in viability between NT3 and C2 cells in response to cisplatin. These results demonstrate a Fas-mediated apoptotic signaling pathway that is enhanced by the age-dependent loss of α(E)-catenin in renal tubule epithelial cells.